Optimization of 2-phenyl-pyrimidine-4-carboxamides towards potent, orally bioavailable and selective P2Y(12) antagonists for inhibition of platelet aggregation

Eva Caroff; Emmanuel Meyer; Alexander Treiber; Kurt Hilpert; Markus A Riederer

doi:10.1016/j.bmcl.2014.06.070

Optimization of 2-phenyl-pyrimidine-4-carboxamides towards potent, orally bioavailable and selective P2Y(12) antagonists for inhibition of platelet aggregation

Bioorg Med Chem Lett. 2014 Sep 1;24(17):4323-31. doi: 10.1016/j.bmcl.2014.06.070. Epub 2014 Jul 1.

Authors

Eva Caroff¹, Emmanuel Meyer², Alexander Treiber², Kurt Hilpert², Markus A Riederer²

Affiliations

¹ Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. Electronic address: eva.caroff@actelion.com.
² Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.

PMID: 25113932
DOI: 10.1016/j.bmcl.2014.06.070

Abstract

2-Phenyl-pyrimidine-4-carboxamide analogs were identified as P2Y12 antagonists. Optimization of the carbon-linked or nitrogen-linked substituent at the 6-position of the pyrimidine ring provided compounds with excellent ex vivo potency in the platelet aggregation assay in human plasma. Compound 23u met the objectives for activity, selectivity and ADMET properties.

Keywords: Antiplatelet; Antithrombotic; GPCR antagonist; P2Y(12) antagonist; P2Y(12) receptor.

MeSH terms

Administration, Oral
Biological Availability
Dose-Response Relationship, Drug
Glutamates / administration & dosage*
Glutamates / chemistry
Glutamates / pharmacology*
Humans
Molecular Structure
Platelet Aggregation / drug effects*
Purinergic P2Y Receptor Antagonists / administration & dosage*
Purinergic P2Y Receptor Antagonists / pharmacology*
Pyrimidines / administration & dosage*
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship

Substances

Glutamates
Purinergic P2Y Receptor Antagonists
Pyrimidines